Infection with the human immunodeficiency virus (HIV) leads to a progressive drop in the number and function of CD4 T cells and the development of the acquired immune deficiency syndrome (AIDS). It is urgent to characterize what factors influence the progression of HIV disease to AIDS in order to develop more effective treatment interventions for HIV+ patients. Progression to AIDS depends in part upon the rate of HIV replication, the host's response to the virus, and other immunosuppressive influences that act as "cofactors" of, the HIV disease process. Animal and human experiments indicate that drugs of abuse can suppress certain immune responses, but rigorous research has not yet tested if these substances are significant cofactors of AIDS. This is the goal of the proposed studies. This is a resubmission of FIRST award application 1 R29 DA07683-01, originally written in response to NIDA Program Announcement Drug Abuse Aspects of AIDS. Preclinical studies were proposed to characterize the direct effects of drugs of abuse on CD4 lymphocytes in vitro, and to describe the mechanisms of these outcomes. These investigations have been expanded: The originally proposed experiments, designed to characterize the direct influence of cocaine and PCP on CD4 cells, will be conducted during Years 01-03 approved by the Committee; a second series of in vivo studies, proposed for Years 04 and 05, will characterize both basal T cell populations and function in cocaine users and the response of T cell distribution and function to alcohol consumption in these subjects. Co-use of cocaine and alcohol is frequent among individuals at risk for HIV infection, and both substances are immunosuppressive. It is hypothesized that joint cocaine and alcohol use impairs CD4 lymphocytes, and may act as an important cofactor of AIDS. The proposed studies will focus on the effects of cocaine because of its prevalence today over PCP. In vitro experiments will test the effects of cocaine and PCP on CD4 cell function and maturation, including molecular processes (i.e., transmembrane and genome events). In vivo investigations will test the effects of experimentally controlled alcohol consumption on T cell responses (distribution, maturation and function, including transmembrane and genome events) in cocaine users and control subjects. Equal number of in each group will be randomly assigned to an "alcohol" or a "placebo" group. Baseline measurements of T cell distri- bution and function will be obtained before the administration of beverage alcohol. Measurements will be repeated at regular intervals thereafter, during the period of time that encompasses the hormonal response to alcohol in normals. Neuroendocrine and psychological correlates will be monitored. Data will be analyzed statistically by ANOVA, repeated measures and logistic regression designs. The proposed studies converge and contribute to the development of my research program, which focuses on determining the role of drugs of abuse as cofactors of AIDS.